This invention relates to a method of regulating secretions in and around the eye of a patient by administering purinergic receptor agonists such as certain uridine, adenine, or cytidine triphosphates as well as other dinucleoside polyphosphate compounds.
This invention also relates to a method of enhancing drainage of the lacrimal system by administering a pharmacologic agent that enhances mucociliary clearance of the nasolacrimal duct of a mammal. These agents include certain uridine, adenine and cytidine triphosphates as well as other dinucleoside polyphosphate compounds.
There are many situations where it is therapeutically desirable to increase the amount of tear fluid produced by the eye. Dry eye disease is the general term for indications produced by abnormalities of the precorneal tear film characterized by a decrease in tear production or an increase in tear film evaporation, together with the ocular surface disease that results. Approximately 38 million Americans are affected with some type of dry eye disorder. Among the indications that are referred to by the general term xe2x80x9cdry eye diseasexe2x80x9d are: keratoconjunctivitis sicca (KCS), age-related dry eye, Stevens-Johnson syndrome, Sjogren""s syndrome, ocular cicatrical pemphigoid, blepharitis, corneal injury, infection, Riley-Day syndrome, congenital alacrima, nutritional disorders or deficiencies (including vitamins), pharmacologic side effects, eye stress and glandular and tissue destruction, environmental exposure to smog, smoke, excessively dry air, airborne particulates, autoimmune and other immunodeficient disorders, and comatose patients rendered unable to blink.
A healthy precorneal tear film has several important functions: 1) to protect the cornea from desiccation; 2) to aid in the immune response to infections; 3) to enhance oxygen permeation into the cornea; and 4) to allow gliding movement of the eyeball and eyelids. There are two structures responsible for maintaining the properties of the tear filmxe2x80x94the lacrimal glands and the conjunctiva (the mucous membrane which surrounds part of the eyeball and inner eyelids). These structures maintain the tear film via regulation of water and electrolyte transport and via mucin release by goblet cells.
The progression of dry eye disease is characterized by four main xe2x80x9cmilestones.xe2x80x9d The first milestone is a decrease in tear production. In rabbit models, this decrease in tear production has been shown to correlate with an increase in tear osmolarity. The second milestone is a loss of mucous-containing conjunctival goblet cells. This decrease in goblet cell density becomes evident several weeks after the onset of decreased tear production. The third milestone in the progression of dry eye disease occurs about 1 year later when desquamation of the corneal epithelium is observed. The fourth and last milestone of the disease is a destabilization of the cornea-tear interface (Gilbard, CLAO Journal, 22(2), 141-45 (1996)).
Currently, the pharmaceutical treatment of dry eye disease is mostly limited to administration of artificial tears (saline solution) to temporarily rehydrate the eyes. However, relief is short-lived and frequent dosing is necessary. In addition, artificial tears often have contraindications and incompatibility with soft contact lenses (Lemp, Cornea, 9(1), S48-550 (1990)). The use of phosphodiesterase inhibitors, such as 3-isobutyl-1-methylxanthine (IBMX) to stimulate tear secretion is disclosed in U.S. Pat. No. 4,753,945. The effectiveness of these phosphodiesterase inhibitors is currently being investigated (Gilbard, et al., Arch. Ophthal, 112, 1614-16 (1994) and 109, 672-76 (1991); idem, Inv. Ophthal. Vis. Sci. 31, 1381-88 (1990)). Stimulation of tear secretion by topical application of melanocyte stimulating hormones is described in U.S. Pat. No. 4,868,154.
There are many situations where it is therapeutically desirable to increase drainage of the lacrimal system. The lacrimal system has two functioning components: the secretory part, which produces tears, and the excretory part, which drains the tears into the nose. When the lacrimal drainage system is not functioning properly the result can be excessive tearing (epiphora), mucopurulent discharge, and recurrent dacryocystitis (Shermataro, et al., JAOA, 94, 229 (1994)). In fact, tearing is one of the most common complaints that brings a patient to the ophthalmologist""s office (Conway, Ophthal. Plas. Reconstr. Surg., 10, 185 (1994)).
The most common malfunction of the lacrimal drainage system is nasolacrimal duct obstruction, which results in stasis of tears in the lacrimal sac. The accumulation of fluid and mucus results in tearing and expulsion of mucopurulent material, causing the eyelids to be xe2x80x9cstuck togetherxe2x80x9d on awakening in the morning. The lack of clearance of the tear fluid also leads to inflammation and chronic infection of the lacrimal sac and ducts (Hyde, et al., Ophthal., 95, 1447 (1988); Blicker, et al., Ophthal. Plas. Reconstr. Surg., 9, 43 (1993); Mauriello Jr., et al., Ophthal. Plast. Reconstr. Surg., 8, 13 (1992)).
Nasolacrimal duct obstruction can be divided into two etiologic classes: primary acquired nasolacrimal duct obstruction (PANDO), which is characterized by hyperplasia and fibrosis of the mucosal epithelium, and secondary acquired nasolacrimal duct obstruction (SANDO), which is caused by cancer, inflammation, infection, trauma and mechanical problems (Bartley, Ophthal. Plast. Reconstr. Surg., 8, 237 (1992)). An occluded nasolacrimal duct is more common in middle-aged women and infants. In fact, up to 20% of all infants are affected by nasolacrimal duct obstruction with most of them becoming symptom free by their first birthday (Young, et al., Eye, 10, 485 (1996)).
Current treatments for nasolacrimal duct obstruction are mostly invasive or surgical procedures that vary in aggressiveness. Intervention can take the form of probing the duct with a fine catheter; however, this is a difficult and delicate procedure that requires special training and equipment (Kassoff, et al., Arch. Ophthal., 113, 1168 (1995); Griffiths, U.S. Pat. Nos. 4,921,485 (1990) and 5,062,831 (1991); Becker, et al., U.S. Pat. Nos. 5,021,043 (1991) and 5,169,386 (1992)). In some cases silastic intubation of the nasolacrimal duct increases drainage of tears through the nasolacrimal duct (Dortzbach, et al., Amer. J Ophthal., 94, 585 (1982); Al-Hussain, et al., Ophthal. Plas. Reconstr. Surg., 9, 32 (1993); Crawford, et al. U.S. Pat. No. 4,380,239 (1983); Ector, Jr., U.S. Pat. No. 4,658,816 (1987)). A more aggressive procedure is a dacryo-cystorhinostomy which surgically creates a new drainage path above the sight of obstruction allowing continuity between the lacrimal sac and the nasal cavity (Linberg, et al., Ophthal., 93, 1055 (1986); Tarbert, Ophthal., 102, 1065 (1995); O""Donnell, Jr., U.S. Pat. No. 5,345,948 (1994)). External massage of the nasolacrimal duct has also been shown to increase tear transit times through the nasolacrimal duct (J. A. Foster, et al., Ophthal. Plas. Reconstr. Surg., 12, 32 (1996)).
Thus, as a result of the ineffectiveness and inconvenience of current therapies, medical researchers have sought to develop alternatives for the treatment of dry eye disorders and nasolacrimal duct disorders. It has been shown that uridine 5xe2x80x2-triphosphate (UTP) and adenine 5xe2x80x2-triphosphate (ATP) are potent agonists of P2Y2 purinergic receptors found on the surface of human airway epithelium. Activation of these P2Y2 purinergic receptors induces chloride and water secretion, helping hydrate the airway surface secretions. Use of UTP and ATP for the purpose of treating pulmonary disorders characterized by the retention of lung mucus secretions is described in U.S. Pat. No. 5,292,498. Because of the demonstrated ability of UTP to increase hydration of airway epithelial secretions, applicants were motivated to investigate whether UTP and other P2Y2 and P2Y4 purinergic receptor agonists could also stimulate hydration of ocular epithelia.
It had previously been shown that P2 type purinergic receptors in rat and mouse lacrimal acinar cells responded to extracellular ATP by increasing intracellular calcium (Sasaki, et al., Febs Lett. 264, 130-34 (1990); idem, J. Physiol,. 447, 103-18 (1992);Vincent, J. Physiol., 449, 313-31 (1992); Gromada, et al., Eur. J. Physiol., 429, 578 (1995); Lee, et al. Inv. Ophthal. Vis. Sci., 38(4)(1997) abstract).
The discovery of diadenosine 5xe2x80x2-polyphosphates (ApnA, n=2-7) and their release from platelets and chromaffin cells has led to many studies of the biological activity and cellular processing of these intra- and extracellular signalling molecules (Pintor, Nervous Control of the Eye, 171-210 (1999); Hoyle et al., Drug Dev Res, 52:260-273 (2001)). Diadenosine polyphosphates have interesting pharmacological effects on nucleotide receptors; that is, depending on the chain length, they may be agonists or antagonists at P2X and P2Y receptors with varying selectivity. There is not a clear relationship between the phosphate chain length and the selective activity on P2X or P2Y receptors; however, from a physiological point of view, some of them can act as vasodilators (Ap2A and Ap3A) while others act as vasoconstrictors (Ap4A, Ap5A and Ap6A) (Ralevic, et al., Pharmacol Rev, 50:413-492 (1998)).
Diadenosine polyphosphates were found to be potent and full agonists in cells overexpressing the human P2Y2 receptor (Lazarowski et al., Br J Pharmacol, 116:1619-1627 (1995). The avian P2Y1 receptor is sensitive to Ap4A, presenting EC50 values in the nM range (Pintor et al., Br J Pharmacol, 119:1006-1012 (1996). Important differences have been observed on native P2Y1 receptors, where diadenosine tetraphosphate behaved as an antagonist in clear contrast with the behavior of this dinucleotide in cloned P2Y1 receptors (Vigne et al., Br J Pharmacol, 129:1506-1512 (2000). On the other hand, other expressed P2Y receptors, such as P2Y4 are also activated by Ap3A-Ap6A in the micromolar range (Communi, et al., Eur J Pharmacol 317:383-389 (1996); Janssens et al., Biochem Biophys Res Commun, 236:106-112 (1997)).
This invention is directed to a method of stimulating tear secretion and mucin production in eyes. The method comprises the step of administering to the eyes of a subject a composition comprising a compound of Formula I, II, III, or IV and its pharmaceutically acceptable salts, in an amount effective to stimulate tear fluid secretion. The method of the present invention may be used to increase tear production for any reason, including, but not limited to, treatment of dry eye disease and corneal injury.
The method of the present invention comprises topically administering a liquid or gel composition comprising an effective amount of a P2Y2 and/or P2Y4 purinergic receptor agonist selected from the group consisting of uridine triphosphate (UTP) and its analogs, P1, P4-di(uridine-5xe2x80x2-)tetraphosphate (U2P4) and its analogs, P1, P4-di(adenosine-5xe2x80x2-)tetraphosphate (A2P4) and its analogs, P1, P5-di(adenosine-5xe2x80x2-)pentaphosphate (A2P5) and its analogs, P1, P6-di(adenosine-5xe2x80x2-)hexaphosphate (A2P6) and its analogs, cytidine 5xe2x80x2-triphosphate (CTP) and its analogs, and adenosine 5xe2x80x2-triphosphate (ATP) and its analogs.
Yet another aspect of the present invention is a pharmaceutical composition comprising a compound of Formula I, II, III, or IV, in a pharmaceutical carrier in an amount effective to stimulate tear production or to enhance clearance of nasolacrimal ducts in a subject in need of such treatment.